Therapeutic challenge during the long-term follow-up of a patient with indolent systemic mastocytosis with extensive cutaneous involvement.

From a dermatological aspect, it posed a considerable challenge the skin-limited form of mastocytosis, urticaria pigmentosa and indolent systemic mastocytosis (ISM) with cutaneous lesions. Despite the favourable prognosis, lifelong dermatological control is needed, during which the average symptomatic therapy does not always seem adequate. We report here the case of a female ISM patient with recurrent cutaneous symptoms that impaired her quality of life, with a follow-up time of 27 years. During this long follow-up period, the cutaneous lesions could be controlled by antihistamines, leukotriene antagonists, glucocorticoids, local immunosuppressants or local UV radiation for only relatively short periods. Imatinib mesylate was, therefore, introduced in an attempt to control the cutaneous lesions. Tyrosine kinase inhibition is an unusual dermatological therapeutic option. This case illustrates that imatinib mesylate was a good choice with which to achieve a reduction of the skin lesions in this KIT D816V mutation-negative disease: it led to a temporary appreciable improvement of the patient's quality of life.

The effect of steroid pulse therapy on carbohydrate metabolism in multiple myeloma patients: a randomized crossover observational clinical study.

BACKGROUND: Hyperglycemia is a common, but not well-characterized side effect of glucocorticoid treatment. AIM: To study the effect of pulse dexamethasone treatment on carbohydrate metabolism among multiple myeloma patients. MATERIAL/SUBJECTS AND METHODS: A randomized crossover observational study in a teaching hospital with nine myeloma patients (one male, two with known type 2 diabetes (KDM), mean age 69.0 ± 6.7 years) were investigated using a standard 75 g Oral Glucose Tolerance Test (patients without KDM) and a 3-day continuous glucose monitoring (CGM--all patients) during and between dexamethasone cycles. RESULTS: During dexamethasone treatment patients had elevated 2-h postload glucose (12.8 ± 4.7 vs. 8.7 ± 3.2 mmol/L, P = 0.024) but similar fasting glucose (6.3 ± 1.4 vs. 5.1 ± 0.5 mmol/L, P = 0.112). Estimated hourly mean interstitial glucose values based on linear mixed models showed an increase of 0.03 [SE 0.01] mmol/L per hour from 5.0 [0.4] in patients without KDM and followed a quadratic curve from 5.0 [0.4] mmol/L at midnight to 7.5 [0.5] mmol/L at 12:00 h in patients with KDM during control periods. During dexamethasone treatment glucose was similar to control periods between 02:00 and 12:00 h in the non-KDM group, where they followed a cubic trajectory from 5.3 [0.4] mmol/L at 04:00 h to 7.3 [0.4] mmol/L at 18:00 h. In contrast, interstitial glucose was increased by at least 7.9 [0.3] mmol/L throughout the day in KDM patients during dexamethasone treatment and increased from 13.6 [0.5] mmol/L at midnight to 17.5 [0.5] mmol/L at 17:00 h. CONCLUSIONS: During pulse steroid therapy of myeloma patients without KDM afternoon and evening glucose measurements may be the optimal tools to characterize glucose metabolism.

Simultaneous polarized neutron reflectometry and anisotropic magnetoresistance measurements.

A novel experimental facility to carry out simultaneous polarized neutron reflectometry (PNR) and anisotropic magnetoresistance (AMR) measurements is presented. Performing both techniques at the same time increases their strength considerably. The proof of concept of this method is demonstrated on a CoO/Co bilayer exchange bias system. Although information on the same phenomena, such as the coercivity or the reversal mechanism, can be separately obtained from either of these techniques, the simultaneous application optimizes the consistency between both. In this way, possible differences in experimental conditions, such as applied magnetic field amplitude and orientation, sample temperature, magnetic history, etc., can be ruled out. Consequently, only differences in the fundamental sensitivities of the techniques can cause discrepancies in the interpretation between the two. The almost instantaneous information obtained from AMR can be used to reveal time-dependent effects during the PNR acquisition. Moreover, the information inferred from the AMR measurements can be used for optimizing the experimental conditions for the PNR measurements in a more efficient way than with the PNR measurements alone.

Activity of the notch-signalling pathway in circulating human chronic lymphocytic leukaemia cells.

Dysregulation of the Notch-pathway has been implicated in the pathogenesis of chronic lymphocytic leukaemia (B-CLL). We characterized the mRNA expression of Notch pathway elements in circulating normal B- and B-CLL cells, and compared expression profiles with clinical and prognostic data. Similar expression profiles were found in normal B-cells and B-CLL cells, however, most B-CLL samples showed lower Hairy/Enhancer of Split-1 expression than normal B-cells, which suggests that the pathway is not over-activated in B-CLL. The expression of Notch-pathway genes did not correlate with other prognostic factors of B-CLL. The importance of Notch-signalling in CLL cells in lymphatic tissue microenvironments remains to be determined.

Metabolism and disposition of 1-bromopropane in rats and mice following inhalation or intravenous administration.

Workplace exposure to 1-bromopropane (1-BrP) can potentially occur during its use in spray adhesives, fats, waxes, and resins. 1-BrP may be used to replace ozone depleting solvents, resulting in an increase in its annual production in the US, which currently exceeds 1 million pounds. The potential for human exposure to 1-BrP and the reports of adverse effects associated with potential occupational exposure to high levels of 1-BrP have increased the need for the development of biomarkers of exposure and an improved understanding of 1-BrP metabolism and disposition. In this study, the factors influencing the disposition and biotransformation of 1-BrP were examined in male F344 rats and B6C3F1 mice following inhalation exposure (800 ppm) or intravenous administration (5, 20, and 100 mg/kg). [1,2,3-(13)C]1-BrP and [1-(14)C]1-BrP were administered to enable characterization of urinary metabolites using NMR spectroscopy, LC-MS/MS, and HPLC coupled radiochromatography. Exhaled breath volatile organic chemicals (VOC), exhaled CO(2), urine, feces, and tissues were collected for up to 48 h post-administration for determination of radioactivity distribution. Rats and mice exhaled a majority of the administered dose as either VOC (40-72%) or (14)CO(2) (10-30%). For rats, but not mice, the percentage of the dose exhaled as VOC increased between the mid ( approximately 50%) and high ( approximately 71%) dose groups; while the percentage of the dose exhaled as (14)CO(2) decreased (19 to 10%). The molar ratio of exhaled (14)CO(2) to total released bromide, which decreased as dose increased, demonstrated that the proportion of 1-BrP metabolized via oxidation relative to pathways dependent on glutathione conjugation is inversely proportional to dose in the rat. [(14)C]1-BrP equivalents were recovered in urine (13-17%, rats; 14-23% mice), feces (<2%), or retained in the tissues and carcass (<6%) of rats and mice administered i.v. 5 to 100 mg/kg [(14)C]1-BrP. Metabolites characterized in urine of rats and mice include N-acetyl-S-propylcysteine, N-acetyl-3-(propylsulfinyl)alanine, N-acetyl-S-(2-hydroxypropyl)cysteine, 1-bromo-2-hydroxypropane-O-glucuronide, N-acetyl-S-(2-oxopropyl)cysteine, and N-acetyl-3-[(2-oxopropyl)sulfinyl]alanine. These metabolites may be formed following oxidation of 1-bromopropane to 1-bromo-2-propanol and bromoacetone and following subsequent glutathione conjugation with either of these compounds. Rats pretreated with 1-aminobenzotriazole (ABT), a potent inhibitor of P450 excreted less in urine (down 30%), exhaled as (14)CO2 (down 80%), or retained in liver (down 90%), with a concomitant increase in radioactivity expired as VOC (up 52%). Following ABT pretreatment, rat urinary metabolites were reduced in number from 10 to 1, N-acetyl-S-propylcysteine, which accounted for >90% of the total urinary radioactivity in ABT pretreated rats. Together, these data demonstrate a role for cytochrome P450 and glutathione in the dose-dependent metabolism and disposition of 1-BrP in the rat.

Familial occurrence of the May-Hegglin anomaly: is the accompanying renal failure part of a new subentity?

We present two cases of the May-Hegglin anomaly discovered in a patient and one of her two sons. The female patient was known to have proteinuria from the age of 14 and was hospitalized in 1980, at the age of 25 years, because of hypertension and proteinuria (1.5 g/day). Thrombocytopenia was found with an abundance of megakaryocytes in the bone marrow. Both steroid treatment and splenectomy failed to ameliorate the thrombocytopenia, thought to be due to idiopathic thrombocytopenic purpura. Progressive renal failure, secondary hyperparathyroidism and uremic osteodystrophy were diagnosed in 1995. In January 1996, when she was hospitalized because of high-grade fever, we saw giant platelets and prominent blue inclusion bodies in almost all granulocytes in the peripheral blood smear. Electron microscopy confirmed the diagnosis of May-Hegglin anomaly in this patient and one of her sons, who at that time showed thrombocytopenia but no renal disease. Three years later, however, at the age of 15, the affected son was found to develop proteinuria. Coexpression of the May-Hegglin anomaly and renal disease, reported previously in a few other patients, may in fact represent a new subentity.

Increased risk for cancer in multiple myeloma patients and their first-degree relatives.

Analyzing data of 125 multiple myeloma patients, the authors found a 40-fold increased tumor incidence among the patients and their first-degree relatives as compared to the average population. These tumors were the same as those usually found among Hungarians. There was no difference as to the patient's blood group antigens in the families of myeloma patients with or without other tumor. IgA-type disease was found to be relatively more frequent in the group of patients who had tumor besides myeloma. In a prospective study, authors could not find mutation of suppressor gene p53 in 14 patients and their 16 healthy first-degree relatives. This may indicate that there is no p53 suppressor gene alteration responsible for the high-risk condition for tumorgenesis in this population.

[Progress in the treatment of non-Hodgkin's lymphomas] / Elôrehaladás a non-Hodgkin-lymphomák kezelésében.

The authors analyze the progress achieved in the treatment of low-grade as well as of high-grade non-Hodgkin's lymphomas. The challenging task in the treatment of low-grade or indolent lymphomas still is to decide whether watchful waiting is sufficient or whether chemotherapy is necessary and how aggressive this treatment should be. Among the new chemotherapeutic agents the role of purine analogues should be emphasized, fludarabin is especially important in the treatment of chronic lymphocytic leukemia and follicular lymphoma, while pentostatin and cladribine have revolutionized the treatment of hairy cell leukemia. Treatment with monoclonal antibodies, radioimmunoconjugates as well as autologous or allogeneic stem cell transplantation are potential new therapeutic options in the treatment of low-grade non-Hodgkin's lymphomas. In the case of aggressive non-Hodgkin's lymphomas risk-adapted strategies help the choice between standard or more intensive treatment options. In patients with relapsed high-grade lymphomas stem cell transplantation is indicated. In patients with marginal zone lymphoma the combination of hyperCVAD protocol + stem cell transplantation greatly improves prognosis.

The DNA damage checkpoint signal in budding yeast is nuclear limited.

The nature of the DNA damage-induced checkpoint signal that causes the arrest of cells prior to mitosis is unknown. To determine if this signal is transmitted through the cytoplasm or is confined to the nucleus, we created binucleate heterokaryon yeast cells in which one nucleus suffered an unrepairable double-strand break, and the second nucleus was undamaged. In most of these binucleate cells, the damaged nucleus arrested prior to spindle elongation, while the undamaged nucleus completed mitosis, even when the strength of the damage signal was increased. The arrest of the damaged nucleus was dependent upon the function of the RAD9 checkpoint gene. Thus, the DNA damage checkpoint causing G2/M arrest is regulated by a signal that is nuclear limited.

[Detection of minimal residual diseases in B-cell tumors using PCR specific for the immunoglobulin heavy chain gene]. / A minimális reziduális betegség kimutatása B-sejtes tumorok esetében az immunglobulin nehézlánc génre specifikus polimeráz láncreakció segítségével.

In B-cell non-Hodgkin's lymphomas (NHL), clonal rearrangement of the immunoglobulin heavy chain (IgH) gene provides a useful marker for the detection of minimal residual disease (MRD) after treatment. To explore clinical usefulness of polymerase chain reaction (PCR) analysis of clonal IgH gene rearrangement in the detection of MRD a follow up study of 10 patients with B-cell NHL have been performed. At the time of diagnosis, tumor DNAs were PCR-amplified using sense primer specific for the heavy chain variable region (VH) and antisense primer specific for the heavy chain joining region (JH) of the IgH gene. The clonal rearrangement of IgH gene detected by PCR was used as clonal marker to determine MRD after treatment. In three cases, where clinical remission was not achieved, clonal IgH gene rearrangement was detected after the treatment. In seven cases, clinical remission was achieved after induction therapy but the PCR analysis revealed clonal IgH gene rearrangement in three of the cases. In all of the three cases, where MRD was detected by PCR, clinical relapse developed after 7-28 months of the therapy. In all cases that have relapsed, the IgH gene rearrangement was identical at the time of initial diagnosis and at the relapse. This study demonstrates that PCR analysis of clonal IgH gene rearrangement is a useful method to monitor and detect MRD before clinical relapse.

p53 mutations in hairy cell leukemia.

We have studied the frequency of p53 mutations in genomic DNA extracted from peripheral blood or the spleen of 61 patients with hairy cell leukemia using PCR-SSCP and automated cycle sequencing. We identified exon 5-8 mutations in 17 cases, corresponding to a frequency of 28%. In four cases, mutations were localized in exon 5; one patient with atypical HCL had a mutation in exon 6 at the 3' boundary; five cases showed mutations in exon 7, while exon 8 was found to be mutated in seven cases. The mutations found could be divided into three major categories: structural (n=9), inactivating (n= 6), and neutral (n= 2) mutations. None of the three transitions found occurred at CpG dinucleotides. The rate of p53 mutations found in this large cohort of HCL patients is unexpectedly high as in other non-Hodgkin lymphomas p53 mutations predict for poor treatment outcome. The character of the mutations we have found is entirely different from that described in other hematologic malignancies.

May-Hegglin anomaly and pregnancy.

A hypertensive patients with thrombocytopenia is reported who had two pregnancies complicated by preeclampsia and cesarean deliveries without hemorrhage. During her first pregnancy corticosteroids were given for presumed autoimmune thrombocytopenia. Thereafter she was splenectomised. Ten years later May-Hegglin anomaly and renal failure were diagnosed. One of her children had easy bruising.

[Long-term results with fludarabine monotherapy in chronic lymphocytic leukemia]. / Fludarabin monoterápiával kezelt krónikus lymphoid leukaemiás betegeink hosszú távú követése során szerzett megfigyeléseink.

Fludarabine has widely been studied in chronic lymphocytic leukemia (CLL), with impressive remission rates in refractory, relapsed or untreated disease. In our study the clinical response and survival of 9 patients with a mean follow-up time of 28 months after treatment with fludarabine as a single agent for CLL has been evaluated. Seven patients were previously treated. Partial remission was achieved in 8 patients. No complete remission was seen. The cytoreductive activity of fludarabine was excellent in all the 9 patients. The median time to progression was 13.5 months. The median survival time from entering the trial was 27.9 months. Our patients tolerated the fludarabine treatment extremely well. Although fludarabine has been established as the most active single agent in CLL, most patients will have recurrent disease. 7/9 patients relapsed in our study, and they were given further chemotherapy. Grade 4 hematologic toxicity was observed in 2 patients. During the fludarabine treatment the frequency of infections decreased, but in the following 12 months increased again. Three fludarabine-treated patients developed high-grade non-Hodgkin lymphoma. It is concluded that fludarabine is a highly useful agent in CLL.

[Morphological parameters of breast cancers detected by mammography with and without organized screening; a comparative study]. / Mammográfiával felismert rákok morphologiai paramétereinek összehasonlítása a területileg szervezett szürés során és alkalomszerüen vizsgáltaknál.

Some pathological findings and prognostic indices recorded in breast cancer cases, detected, on one hand, by a provider-initiated mammography screening program (Group 1), and, opportunistically, in self-referred symptomatic women (Group 2) on the other, are compared. In 8877 symptom-free women, aged 50-65 years, individually invited to attend the screening offered for the residents of the III., XII. and XIII. districts of Budapest, 67 cancer cases were detected (7.5 in 1000 screenees), in accordance with the cancer detection rate of the first, "prevalence" round of organised screening programmes. In the other group of 1593 symptomatic, self-referred women of the same age, 113 cancer cases were diagnosed by mammography. As far as the pathological parameters are concerned, the number of cases with invasive cancer less than 15 mm in diameter, and those with axillary nodes present was found to be significantly higher in the screened group as compared to the self-referred one (p < 0.01). In "small" cancers (i.e. less than 15 mm in diameter), no significant difference was found in the proportion of histologic grade III tumours among the two groups. In screen-detected cancers both the morphometric prognostic index (as calculated by Baak et al.) and the Nottingham Prognostic Index (NPI) proved to be more favourable, as compared to those in the self-referred group. The p-value as determined by Mann-Whithey test was 0.000003 in the screened group, and 0.000015 in the other one. These findings provide convincing evidence in support of the public health importance of provider-initiated, organised mammography screening for breast cancer, therefore, the introduction on service basis of organised breast screening into the health care system in Hungary is strongly recommended by the authors.

imp2, a new component of the actin ring in the fission yeast Schizosaccharomyces pombe.

Cytokinesis is the part of the cell cycle in which the cell is cleaved to form two daughter cells. The unicellular yeast, Schizosaccharomyces pombe is an excellent model organism in which to study cell division, since it shows the general features of eukaryotic cell division and is amenable to genetic analysis. In this manuscript we describe the isolation and characterization of a new protein, imp2, which is required for normal septation in fission yeast. imp2, which colocalizes with the medial ring during septation, is structurally similar to a group of proteins including the S. pombe cdc15 and the mouse PSTPIP that are localized to, and thought to be involved in actin ring organization. Cells in which the imp2 gene is deleted or overexpressed have septation and cell separation defects. An analysis of the actin cytoskeleton shows the lack of a medial ring in septating cells that overexpress imp2, and the appearance of abnormal medial ring structures in septated cells that lack imp2. These observations suggest that imp2 destabilizes the medial ring during septation. imp2 also shows genetic interactions with several, previously characterized septation genes, strengthening the conclusion that it plays a role in normal fission yeast septation.

Isolation and characterization of fission yeast sns mutants defective at the mitosis-to-interphase transition.

pim1-d1ts was previously identified in a visual screen for fission yeast mutants unable to complete the mitosis-to-interphase transition. pim1+ encodes the guanine nucleotide exchange factor (GEF) for the spi1 GTPase. Perturbations of this GTPase system by either mutation or overproduction of its regulatory proteins cause cells to arrest with postmitotic condensed chromosomes, an unreplicated genome, and a wide medial septum. The septation phenotype of pim1-d1ts was used as the basis for a more extensive screen for this novel class of sns (septated, not in S-phase) mutants. Seventeen mutants representing 14 complementation groups were isolated. Three strains, sns-A3, sns-A5, and sns-A6, representing two different alleles, are mutated in the pim1+ gene. Of the 13 non-pim1ts sns complementation groups, 11 showed genetic interactions with the spi1 GTPase system. The genes mutated in 10 sns strains were synthetically lethal with pim1-d1, and six sns strains were hypersensitive to overexpression of one or more of the known components of the spil GTPase system. Epistasis analysis places the action of the genes mutated in nine of these strains downstream of pim1+ and the action of one gene upstream of pim1+. Three strains, sns-A2, sns-B1, and sns-B9, showed genetic interaction with the spil GTPase system in every test performed. sns-B1 and sns-B9 are likely to identify downstream targets, whereas sns-A2 is likely to identify upstream regulators of the spi1 GTPase system that are required for the mitosis-to-interphase transition.